Human-Endogenous Virus-Like Particles for Lower-Immunogenicity Cargo Delivery
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Solution Overview
Problem
Current methods for delivering cargo such as proteins, nucleic acids, and chemicals into the cytosol of living cells are inefficient, unsafe, and immunogenic, particularly for genome editing reagents like CRISPR-Cas9, due to issues with immunogenicity, off-target effects, and limited packaging capacity of existing viral and nanoparticle-based systems.
Innovation Solution
Development of engineered human-endogenous virus-like particles (heVLPs) composed of a phospholipid bilayer and human-derived components, which can package and deliver DNA, RNA, proteins, and chemicals without exogenous viral proteins, using human-endogenous GAG and ENV proteins for efficient cellular uptake and minimizing immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If viral particle-based delivery systems are used, then delivery efficiency is improved, but immunogenicity increases
Solution Approach 1:
The patent extracts and removes the immunogenic viral proteins (gag and pol) from the delivery system while retaining the essential virus-like particle structure and cargo delivery capability. This creates a simplified system that maintains efficiency without the harmful immunogenic components.
Solution Approach 2:
The patent introduces human-endogenous retroviral envelope proteins as intermediary components that mediate cellular uptake and cargo delivery without triggering immune responses. These endogenous proteins serve as safe mediators that replace the immunogenic viral proteins while maintaining delivery function.
2Reliability
If conventional nanoparticle systems are used, then safety is improved, but delivery efficiency decreases
Solution Approach 1:
The patent creates a composite delivery system that combines the safety of non-viral nanoparticles with the efficiency of viral particles. The heVLP structure integrates human-endogenous proteins with engineered cargo compartments, achieving both safety and high delivery efficiency through this composite architecture.
3Quantity of substance
If exogenous viral proteins are included, then packaging capacity is improved, but immunogenicity increases
Solution Approach 1:
The patent applies local quality by using human-endogenous proteins specifically at the viral interface components (envelope and structural proteins) where they contact the host cell, while maintaining cargo capacity. This localized use of endogenous proteins minimizes immunogenicity at the critical interaction interface while preserving packaging function.
4Reliability
If larger DNA constructs are delivered, then therapeutic efficacy is improved, but delivery difficulty increases
Solution Approach 1:
The patent changes the physical and chemical parameters of the delivery system by using human-endogenous retroviral proteins that naturally accommodate large DNA constructs. The heVLP structure modifies particle size, charge, and stability parameters to enable efficient packaging and delivery of large therapeutic DNA while simplifying the overall delivery process.
Data Source
AI summary
Human-derived virus-like particles (heVLPs), comprising a membrane comprising a phospholipid bilayer with one or more HERV-derived envelope proteins on the external side; one or more HERV-derived GAG proteins in the heVLP core, and a cargo molecule, e.g., a biomolecule and/or chemical cargo molecule, disposed in the core of the heVLP on the inside of the membrane, wherein the heVLP does not comprise a gag protein, except for gag proteins that are encoded in the human genome or gag proteins that are encoded by a consensus sequence that is derived from gag proteins found in the human genome, and methods of use thereof for delivery of the cargo molecule to cells.